The notion of searchable encrypted keywords introduced an elegant approach to retrieve encrypted data without the need of decryption. Since the introduction of this notion, there are two main searchable encrypted keyw...The notion of searchable encrypted keywords introduced an elegant approach to retrieve encrypted data without the need of decryption. Since the introduction of this notion, there are two main searchable encrypted keywords techniques, symmetric searchable encryption (SSE) and public key encryption with keyword search (PEKS). Due to the complicated key management problem in SSE, a number of concrete PEKS constructions have been proposed to overcome it. However, the security of these PEKS schemes was only weakly defined in presence of outsider attacks;therefore they suffer from keyword guessing attacks from the database server as an insider. How to resist insider attacks remains a challenging problem. We propose the first searchable encrypted keywords against insider attacks (SEK-IA) framework to address this problem. The security model of SEK-IA under public key environment is rebuilt. We give a concrete SEK-IA construction featured with a constant-size trapdoor and the proposed scheme is formally proved to be secure against insider attacks. The performance evaluations show that the communication cost between the receiver and the server in our SEK-IA scheme remains constant, independent of the sender identity set size, and the receiver needs the minimized computational cost to generate a trapdoor to search the data from multiple senders.展开更多
Breast cancer is the most commonly diagnosed cancer type and the leading cause of cancer-related deaths among women worldwide.Previous studies have reported contradictory performance of chemokine CXC motif ligand 13(C...Breast cancer is the most commonly diagnosed cancer type and the leading cause of cancer-related deaths among women worldwide.Previous studies have reported contradictory performance of chemokine CXC motif ligand 13(CXCL13)in breast cancer.In this study,The Cancer Genome Atlas database analysis revealed that CXCL13 was overexpressed in various human cancers including breast carcinoma,and associated with good clinical prognosis in breast cancer.Flow cytometry detection also found upregulated intracellular CXCL13 expression in human breast cancer cell lines.To explore the possible role of CXCL13 in the breast cancer microenvironment,mouse triple negative breast cancer(TNBC)was lentivirally transfected to stably overexpress mouse CXCL13(4T1-CXCL13).Both parental 4T1 and 4T1-CXCL13 strains showed no in vitro or in vivo endogenous cell surface CXCR5 expression.In immune-competent BALB/c mice,the in vivo tumor growth of 4T1-CXCL13 was significantly inhibited and even completely eradicated,accompanied with increased infiltrations of CD4^(+),CD8^(+)T lymphocytes and CD11b^(+)CD11c^(+)DCs.Further investigations showed that CXCL13 expression in the 4T1 tumor microenvironment elicited long-term antitumor immune memory,and rejection of distal parental tumor.The antitumor activity of CXCL13 was remarkedly impaired in BALB/cA-nu nude mice,or in BALB/c mice with CD8^(+)T lymphocyte or NK cell depletion.Our investigation indicated that CXCL13 expression in TNBC triggered effective antitumor immunity by chemoattracting immune cell infiltrations and could be considered as a novel prognostic marker for TNBC.展开更多
Pleural and peritoneal metastasis accompanied by malignant pleural effusion(MPE)or malignant ascites(MA)is frequent in patients with advanced solid tumors that originate from the lung,breast,gastrointestinal tract and...Pleural and peritoneal metastasis accompanied by malignant pleural effusion(MPE)or malignant ascites(MA)is frequent in patients with advanced solid tumors that originate from the lung,breast,gastrointestinal tract and ovary.Regional delivery of CAR-T cells represents a new strategy to control tumor dissemination in serous cavities.However,malignant effusions constitute an immune-suppressive environment that potentially induces CAR-T cell dysfunction.Here,we demonstrated that the anti-tumor cytotoxicity of conventional 2nd-generation CAR-T cells was significantly inhibited by both the cellular and non-cellular components of MPE/MA,which was primarily attributed to impaired CAR-T cell proliferation and cytokine production in MPE/MA environment.Interestingly,we found that PD-L1 was widely expressed on freshly-isolated MPE/MA cells.Based on this feature,a novel PD-L1-targeting chimeric switch receptor(PD-L1.BB CSR)was designed,which can bind to PD-L1,switching the inhibitory signal into an additional 4-1BB signal.When co-expressed with a 2nd-generation CAR,PD-L1.BB CSR-modified CAR-T cells displayed superior fitness and enhanced functions in both culture medium and MPE/MA environment,causing rapid and durable eradication of pleural and peritoneal metastatic tumors in xenograft models.Further investigations revealed elevated expressions of T-cell activation,proliferation,and cytotoxicity-related genes,and we confirmed that PD-L1 scFv and 4-1BB intracellular domain,the two important components of PD-L1.BB CSR,were both necessary for the functional improvements of CAR-T cells.Overall,our study shed light on the clinical application of PD-L1.BB CSR-modified dual-targeting CAR-T cells.Based on this study,a phase I clinical trial was initiated in patients with pleural or peritoneal metastasis(NCT04684459).展开更多
基金This work is supported by the National Natural Science Foundation of China under Grant Nos. 61300181 and 61502044, and the Fundamental Research Funds for the Central Universities of China under Grant No. 2015RC23.
文摘The notion of searchable encrypted keywords introduced an elegant approach to retrieve encrypted data without the need of decryption. Since the introduction of this notion, there are two main searchable encrypted keywords techniques, symmetric searchable encryption (SSE) and public key encryption with keyword search (PEKS). Due to the complicated key management problem in SSE, a number of concrete PEKS constructions have been proposed to overcome it. However, the security of these PEKS schemes was only weakly defined in presence of outsider attacks;therefore they suffer from keyword guessing attacks from the database server as an insider. How to resist insider attacks remains a challenging problem. We propose the first searchable encrypted keywords against insider attacks (SEK-IA) framework to address this problem. The security model of SEK-IA under public key environment is rebuilt. We give a concrete SEK-IA construction featured with a constant-size trapdoor and the proposed scheme is formally proved to be secure against insider attacks. The performance evaluations show that the communication cost between the receiver and the server in our SEK-IA scheme remains constant, independent of the sender identity set size, and the receiver needs the minimized computational cost to generate a trapdoor to search the data from multiple senders.
基金Thisworkwas supported by theNationalNatural Science Foundation of China(grant No.81402354).
文摘Breast cancer is the most commonly diagnosed cancer type and the leading cause of cancer-related deaths among women worldwide.Previous studies have reported contradictory performance of chemokine CXC motif ligand 13(CXCL13)in breast cancer.In this study,The Cancer Genome Atlas database analysis revealed that CXCL13 was overexpressed in various human cancers including breast carcinoma,and associated with good clinical prognosis in breast cancer.Flow cytometry detection also found upregulated intracellular CXCL13 expression in human breast cancer cell lines.To explore the possible role of CXCL13 in the breast cancer microenvironment,mouse triple negative breast cancer(TNBC)was lentivirally transfected to stably overexpress mouse CXCL13(4T1-CXCL13).Both parental 4T1 and 4T1-CXCL13 strains showed no in vitro or in vivo endogenous cell surface CXCR5 expression.In immune-competent BALB/c mice,the in vivo tumor growth of 4T1-CXCL13 was significantly inhibited and even completely eradicated,accompanied with increased infiltrations of CD4^(+),CD8^(+)T lymphocytes and CD11b^(+)CD11c^(+)DCs.Further investigations showed that CXCL13 expression in the 4T1 tumor microenvironment elicited long-term antitumor immune memory,and rejection of distal parental tumor.The antitumor activity of CXCL13 was remarkedly impaired in BALB/cA-nu nude mice,or in BALB/c mice with CD8^(+)T lymphocyte or NK cell depletion.Our investigation indicated that CXCL13 expression in TNBC triggered effective antitumor immunity by chemoattracting immune cell infiltrations and could be considered as a novel prognostic marker for TNBC.
基金National Science and Technology Major Project(2018ZX09733001-003-004)National Natural Science Foundation of China(81673001 and 81872489).
文摘Pleural and peritoneal metastasis accompanied by malignant pleural effusion(MPE)or malignant ascites(MA)is frequent in patients with advanced solid tumors that originate from the lung,breast,gastrointestinal tract and ovary.Regional delivery of CAR-T cells represents a new strategy to control tumor dissemination in serous cavities.However,malignant effusions constitute an immune-suppressive environment that potentially induces CAR-T cell dysfunction.Here,we demonstrated that the anti-tumor cytotoxicity of conventional 2nd-generation CAR-T cells was significantly inhibited by both the cellular and non-cellular components of MPE/MA,which was primarily attributed to impaired CAR-T cell proliferation and cytokine production in MPE/MA environment.Interestingly,we found that PD-L1 was widely expressed on freshly-isolated MPE/MA cells.Based on this feature,a novel PD-L1-targeting chimeric switch receptor(PD-L1.BB CSR)was designed,which can bind to PD-L1,switching the inhibitory signal into an additional 4-1BB signal.When co-expressed with a 2nd-generation CAR,PD-L1.BB CSR-modified CAR-T cells displayed superior fitness and enhanced functions in both culture medium and MPE/MA environment,causing rapid and durable eradication of pleural and peritoneal metastatic tumors in xenograft models.Further investigations revealed elevated expressions of T-cell activation,proliferation,and cytotoxicity-related genes,and we confirmed that PD-L1 scFv and 4-1BB intracellular domain,the two important components of PD-L1.BB CSR,were both necessary for the functional improvements of CAR-T cells.Overall,our study shed light on the clinical application of PD-L1.BB CSR-modified dual-targeting CAR-T cells.Based on this study,a phase I clinical trial was initiated in patients with pleural or peritoneal metastasis(NCT04684459).